Population pharmacokinetics of ivermectin after mass drug administration in lymphatic filariasis endemic communities of Tanzania.

Ivermectin (IVM) is a drug of choice used with albendazole for mass drug administration (MDA) to halt transmission of lymphatic filariasis. We investigated IVM pharmacokinetic (PK) variability for its dose optimization during MDA. PK samples were collected at 0, 2, 4, and 6 h from individuals weighing greater than 15 kg (n = 468) receiving IVM (3-, 6-, 9-, or 12 mg) and ALB (400 mg) during an MDA campaign in Tanzania. Individual characteristics, including demographics, laboratory/clinical parameters, and pharmacogenetic variations were assessed. IVM plasma concentrations were quantified by liquid-chromatography tandem mass spectrometry and analyzed using population-(PopPK) modeling. A two-compartment model with transit absorption kinetics, and allometrically scaled oral clearance (CL/F) and central volume (Vc /F) was adapted. Fitting of the model to the data identified 48% higher bioavailability for the 3 mg dose compared to higher doses and identified a subpopulation with 97% higher mean transit time (MTT). The final estimates for CL/F, Vc /F, intercompartment clearance, peripheral volume, MTT, and absorption rate constant for a 70 kg person (on dose other than 3 mg) were 7.7 L/h, 147 L, 20.4 L/h, 207 L, 1.5 h, and 0.71/h, respectively. Monte-Carlo simulations indicated that weight-based dosing provides comparable exposure across weight bands, but height-based dosing with capping IVM dose at 12 mg for individuals with height greater than 160 cm underdoses those weighing greater than 70 kg. Variability in IVM PKs is partly explained by body weight and dose. The established PopPK model can be used for IVM dose optimization. Height-based pole dosing results in varying IVM exposure in different weight bands, hence using weighing scales for IVM dosing during MDA is recommended.

Genetic and non-genetic factors influencing efavirenz population pharmacokinetics among human immunodeficiency virus-1-infected children in Ethiopia.

Despite the potential for efavirenz (EFV) to be an effective alternative antiretroviral agent, its sources of wide inter- and intra-individual pharmacokinetic (PK) variability are not well-characterized in children. We investigated the effects of genetic and non-genetic factors, including demographic, treatment duration, baseline clinical, and biochemical characteristics, on the PKs of EFV through population-PK modeling. Antiretroviral therapy (ART) naïve HIV infected children, 3-16 years (n = 100), were enrolled in Ethiopia and received EFV-based combination ART. EFV concentrations after the first dose and at steady-state collected over a span of 1 year were modeled using population-based methods. A one-compartment model with first-order absorption kinetics described the observed EFV data adequately. The CYP2B6*6 and ABCB1c.4036A>G genotypes were identified as major factors influencing EFV clearance. The typical estimates of oral clearance, volume of distribution, and absorption rate constant for typical 22 kg children with CYP2B6 *1/*1 and ABCB1c.4036G/G genotypes were 4.3 L/h, 124 L, and 0.776/h, respectively. Clearance was reduced by 28% and 72% in CYP2B6*1/*6 and CYP2B6*6/*6 genotypes, respectively. Compared to week 1, clearance was higher from weeks 8 and 12 in CYP2B6*1/*6 and CYP2B6*1/*1 genotypes, respectively. Simulations indicated that EFV 12-h concentrations were comparable across weight bands, but more than 80% of subjects with CYP2B6*6/*6 had EFV concentrations greater than 4 µg/mL. EFV PK variability among children is partly explained by body weight, treatment duration, CYP2B6*6, and ABCB1 rs3842 genotypes. Therefore, in addition to body weight, pediatric dosing of EFV should consider pharmacogenetic variability, duration of therapy, and individual treatment outcomes.

FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes.

On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.

Model-Informed Drug Development Approaches to Assist New Drug Development in the COVID-19 Pandemic.

Leveraging limited clinical and nonclinical data through modeling approaches facilitates new drug development and regulatory decision making amid the coronavirus disease 2019 (COVID-19) pandemic. Model-informed drug development (MIDD) is an essential tool to integrate those data and generate evidence to (i) provide support for effectiveness in repurposed or new compounds to combat COVID-19 and dose selection when clinical data are lacking; (ii) assess efficacy under practical situations such as dose reduction to overcome supply issues or emergence of resistant variant strains; (iii) demonstrate applicability of MIDD for full extrapolation to adolescents and sometimes to young pediatric patients; and (iv) evaluate the appropriateness for prolonging a dosing interval to reduce the frequency of hospital visits during the pandemic. Ongoing research activities of MIDD reflect our continuous effort and commitment in bridging knowledge gaps that leads to the availability of effective treatments through innovation. Case examples are presented to illustrate how MIDD has been used in various stages of drug development and has the potential to inform regulatory decision making.

Whole Body PBPK Modeling of Remdesivir and Its Metabolites to Aid in Estimating Active Metabolite Exposure in the Lung and Liver in Patients With Organ Dysfunction.

Remdesivir (RDV) is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of coronavirus disease 2019 (COVID-19) in certain patients requiring hospitalization. As a nucleoside analogue prodrug, RDV undergoes intracellular multistep activation to form its pharmacologically active species, GS-443902, which is not detectable in the plasma. A question arises that whether the observed plasma exposure of RDV and its metabolites would correlate with or be informative about the exposure of GS-443902 in tissues. A whole body physiologically-based pharmacokinetic (PBPK) modeling and simulation approach was utilized to elucidate the disposition mechanism of RDV and its metabolites in the lungs and liver and explore the relationship between plasma and tissue pharmacokinetics (PK) of RDV and its metabolites in healthy subjects. In addition, the potential alteration of plasma and tissue PK of RDV and its metabolites in patients with organ dysfunction was explored. Our simulation results indicated that intracellular exposure of GS-443902 was decreased in the liver and increased in the lungs in subjects with hepatic impairment relative to the subjects with normal liver function. In subjects with severe renal impairment, the exposure of GS-443902 in the liver was slightly increased, whereas the lung exposure of GS-443902 was not impacted. These predictions along with the organ impairment study results may be used to support decision making regarding the RDV dosage adjustment in these patient subgroups. The modeling exercise illustrated the potential of whole body PBPK modeling to aid in decision making for nucleotide analogue prodrugs, particularly when the active metabolite exposure in the target tissues is not available.

Predictors of Efavirenz Plasma Exposure, Auto-Induction Profile, and Effect of Pharmacogenetic Variations among HIV-Infected Children in Ethiopia: A Prospective Cohort Study.

(1) Background: Efavirenz plasma concentration displays wide between-patient variability partly due to pharmacogenetic variation and autoinduction. Pediatric data on efavirenz pharmacokinetics and the relevance of pharmacogenetic variation are scarce, particularly from sub-Saharan Africa, where >90% of HIV-infected children live and population genetic diversity is extensive. We prospectively investigated the short- and long-term effects of efavirenz auto-induction on plasma drug exposure and the influence of pharmacogenetics among HIV-infected Ethiopian children. (2) Method: Treatment-naïve HIV-infected children aged 3-16 years old (n = 111) were enrolled prospectively to initiate efavirenz-based combination antiretroviral therapy (cART). Plasma efavirenz concentrations were quantified at 4, 8, 12, 24, and 48 weeks of cART. Genotyping for CYP2B6, CYP3A5, UGT2B7, ABCB1, and SLCO1B1 common functional variant alleles was performed. (3) Results: The efavirenz plasma concentration reached a peak at two months, declined by the 3rd month, and stabilized thereafter, with no significant difference in geometric mean over time. On average, one-fourth of the children had plasma efavirenz concentrations ≥4 µg/mL. On multivariate analysis, CYP2B6*6 and ABCB1c.3435 C > T genotypes and low pre-treatment low-density lipoprotein (LDL) were significantly associated with higher plasma efavirenz concentration regardless of treatment duration. Duration of cART, sex, age, nutritional status, weight, and SLCO1B, CYP3A5, UGT2B7, and ABCB1 rs3842 genotypes were not significant predictors of efavirenz plasma exposure. (4) Conclusion: Pre-treatment LDL cholesterol and CYP2B6*6 and ABCB1c.3435 C > T genotypes predict efavirenz plasma exposure among HIV-infected children, but treatment-duration-dependent changes in plasma efavirenz exposure due to auto-induction are not statistically significant.

Optimal single sampling time-point for monitoring of praziquantel exposure in children.

Praziquantel pharmacokinetics studies in schistosomiasis infected children are scarce partly due to the challenges/complexity of intensive blood sampling in the target population. This study was aimed to investigate the optimal single sampling time-point for monitoring praziquantel exposure. This was intensive pharmacokinetic study conducted among 32 Schistosoma mansoni infected children treated with an oral standard single-dose 40 mg/kg praziquantel. Plasma samples were collected at 0, 1, 2, 4, 6 and 8 h post-praziquantel administration. Quantification of praziquantel and its enantiomers (R- and S-praziquantel) concentrations was done by Liquid chromatography-tandem mass spectrometer (LC-MS/MS). The correlation between area under the plasma concentration-time curve from 0 to 8 h (AUC8) and plasma concentrations at each specific sampling time-point was determined by Pearson's correlation coefficient (r2). The median age (range) of the study population was 12.5 years (10-17). The study participants were 17 males and 15 females. Both total praziquantel and its enantiomers (R- and S-praziquantel) displayed a wide inter-individual pharmacokinetic variability. Regression analysis indicated that, plasma concentrations collected at 4 h post-dose had a significantly highest correlation with the AUC8 for both total praziquantel (r2 = 0.81, p < 0.001) and S-praziquantel (r2 = 0.84, p < 0.001) than any other sampling time-point; while for R-praziquantel, plasma concentrations collected at 6 h sampling time-point had a significantly highest correlation with the AUC8 (r2 = 0.79, p < 0.001) than any other sampling time-point. Four hours sampling time-point post-praziquantel administration is ideal optimal single sampling time-point for therapeutic monitoring of total praziquantel exposure while 6 h sampling time-point is suitable for monitoring of a pharmacologically active R-praziquantel enantiomer.

Anti-SARS-CoV-2 Repurposing Drug Database: Clinical Pharmacology Considerations.

A critical step to evaluate the potential in vivo antiviral activity of a drug is to connect the in vivo exposure to its in vitro antiviral activity. The Anti-SARS-CoV-2 Repurposing Drug Database is a database that includes both in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic data to facilitate the extrapolation from in vitro antiviral activity to potential in vivo antiviral activity for a large set of drugs/compounds. In addition to serving as a data source for in vitro anti-SARS-CoV-2 activity and in vivo pharmacokinetic information, the database is also a calculation tool that can be used to compare the in vitro antiviral activity with in vivo drug exposure to identify potential anti-SARS-CoV-2 drugs. Continuous development and expansion are feasible with the public availability of this database.

Effect of Body Weight and Age on the Pharmacokinetics of Dihydroartemisinin: Food and Drug Administration Basis for Dose Determination of Artesunate for Injection in Pediatric Patients With Severe Malaria.

For treatment of severe malaria, the World Health Organization recommends 3 mg/kg intravenous artesunate in pediatric patients weighing less than 20 kg. Here we describe the Food and Drug Administration's rationale for selecting 2.4 mg/kg in pediatric patients weighing less than 20 kg based on literature review and independent analyses.

Parasite clearance, cure rate, post-treatment prophylaxis and safety of standard 3-day versus an extended 6-day treatment of artemether-lumefantrine and a single low-dose primaquine for uncomplicated Plasmodium falciparum malaria in Bagamoyo district, Tanzania: a randomized controlled trial.

BACKGROUND: Artemisinin-based combination therapy (ACT) resistant Plasmodium falciparum represents an increasing threat to Africa. Extended ACT regimens from standard 3 to 6 days may represent a means to prevent its development and potential spread in Africa. METHODS: Standard 3-day treatment with artemether-lumefantrine (control) was compared to extended 6-day treatment and single low-dose primaquine (intervention); in a randomized controlled, parallel group, superiority clinical trial of patients aged 1-65 years with microscopy confirmed uncomplicated P. falciparum malaria, enrolled in Bagamoyo district, Tanzania. The study evaluated parasite clearance, including proportion of PCR detectable P. falciparum on days 5 and 7 (primary endpoint), cure rate, post-treatment prophylaxis, safety and tolerability. Clinical, and laboratory assessments, including ECG were conducted during 42 days of follow-up. Blood samples were collected for parasite detection (by microscopy and PCR), molecular genotyping and pharmacokinetic analyses. Kaplan-Meier survival analyses were done for both parasite clearance and recurrence. RESULTS: A total of 280 patients were enrolled, 141 and 139 in the control and intervention arm, respectively, of whom 121 completed 42 days follow-up in each arm. There was no difference in proportion of PCR positivity across the arms at day 5 (80/130 (61.5%) vs 89/134 (66.4%), p = 0.44), or day 7 (71/129 (55.0%) vs 70/134 (52.2%), p = 0.71). Day 42 microscopy determined cure rates (PCR adjusted) were 97.4% (100/103) and 98.3% (110/112), p = 0.65, in the control and intervention arm, respectively. Microscopy determined crude recurrent parasitaemia during follow-up was 21/121 (17.4%) in the control and 14/121 (11.6%) in the intervention arm, p = 0.20, and it took 34 days and 42 days in the respective arms for 90% of the patients to remain without recurrent parasitaemia. Lumefantrine exposure was significantly higher in intervention arm from D3 to D42, but cardiac, biochemical and haematological safety was high and similar in both arms. CONCLUSION: Extended 6-day artemether-lumefantrine treatment and a single low-dose of primaquine was not superior to standard 3-day treatment for ACT sensitive P. falciparum infections but, importantly, equally efficacious and safe. Thus, extended artemether-lumefantrine treatment may be considered as a future treatment regimen for ACT resistant P. falciparum, to prolong the therapeutic lifespan of ACT in Africa. Trial registration ClinicalTrials.gov, NCT03241901. Registered July 27, 2017 https://clinicaltrials.gov/show/NCT03241901.

Long-term efavirenz pharmacokinetics is comparable between Tanzanian HIV and HIV/Tuberculosis patients with the same CYP2B6*6 genotype.

The impact of anti-tuberculosis co-treatment on efavirenz (EFV) exposure is still uncertain as contradictory reports exist, and the relevance of CYP2B6*6 genetic polymorphism on efavirenz clearance while on-and-off anti-tuberculosis co-treatment is not well investigated. We investigated the determinants of long-term efavirenz pharmacokinetics by enrolling HIV (n = 20) and HIV/Tuberculosis (n = 36) subjects undergoing efavirenz and efavirenz/rifampicin co-treatment respectively. Pharmacokinetic samplings were done 16 weeks after initiation of efavirenz-based anti-retroviral therapy and eight weeks after completion of rifampicin-based anti-tuberculosis treatment. Population pharmacokinetic modeling was used to characterize variabilities and covariates of efavirenz pharmacokinetic parameters. CYP2B6*6 genetic polymorphism but not rifampicin co-treatment was the statistically significant covariate. The estimated typical efavirenz clearance in the HIV only subjects with the CYP2B6*1/*1 genotype was 23.6 L/h/70 kg, while it was 38% and 69% lower in subjects with the CYP2B6*1/*6 and *6/*6 genotypes, respectively. Among subjects with the same CYP2B6 genotypes, efavirenz clearances were comparable between HIV and HIV/Tuberculosis subjects. Typical efavirenz clearances before and after completion of anti-tuberculosis therapy were comparable. In conclusion, after 16 weeks of treatment, efavirenz clearance is comparable between HIV and HIV/Tuberculosis patients with the same CYP2B6 genotype. CYP2B6 genotyping but not anti-tuberculosis co-treatment should guide efavirenz dosing to optimize treatment outcomes.

Comparative evaluation of pharmacokinetics and pharmacodynamics of insulin glargine (Glaritus®) and Lantus® in healthy subjects: a double-blind, randomized clamp study.

AIMS: The objective of the study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) properties of an insulin glargine formulation, Glaritus® (test) with the innovator's formulation Lantus® (reference) using the euglycemic clamp technique in a single-dose, double-blind, randomized, two sequences, four-period replicate crossover study in healthy volunteers (n = 40). METHODS: Subjects received subcutaneous administration of the insulin glargine (0.4 IU/kg) formulation at two occasions for test and reference and a 20% glucose solution was infused at variable rate to maintain euglycemia for 24 h. RESULTS: Both PK [area under the plasma concentration time curve (AUC0-24 h) and maximum insulin concentration (Cmax)] and PD endpoints [area under glucose infusion rate time curve (AUCGIR0-24) and maximum glucose infusion rate (GIRmax)] demonstrated bioequivalence of Glaritus to Lantus with the 90% confidence interval of geometric mean ratio of test to reference entirely contained within 0.80-1.25. Both formulations showed equivalent geometric least-square mean LSM value (0.08 nmol/L) for Cmax. The geometric LSM AUC0-24 h value for Glaritus® (1.09 h nmol/L) was comparable to Lantus (1.05 h nmol/L). Median Tmax values were also identical (12 h for both), and median t1/2 values were also equal (18 h for both). For GIRTmax, the difference between the means for the two was not statistically significant. No AEs related to study formulations were reported, and both products were well tolerated. CONCLUSIONS: The test product (Glaritus) was found to be bioequivalent to the reference product (Lantus). CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2015/06/005890; http://www.ctri.nic.in/ .